This invention relates to a positionally adjustable set of multiple probes particularly suitable for delivering multiple liquid samples, a system incorporating the probes and a process for utilizing the probes.
Prior to the present invention, robots have been used in numerous applications to reduce the labor required for repetitive sample processing. One such application involves processing and spotting samples for analysis by mass spectrometry (MS) from micro titer plates (MTP) on to Matrix-Assisted Laser/Desorption Ionization (MALDI) sample plates. Historically to assure proper sample spotting a robot end-user doing MALDI MS would need to conduct a height calibration for specific sample plates in specific racks on the robot deck to xe2x80x9cteachxe2x80x9d the robot where the surface of the sample plate was located in relation to the outlet end of a hollow robotic probe. Having determined the height calibration, the robot would attempt to dispense a small volume of liquid onto the surface of the plate by positioning the hollow probe containing a liquid sample just above the surface and then allowing a hanging drop of the sample to touch the surface, thus causing it to stick and be deposited on the surface. Robotic workstations can hold many racks, which typically hold many sample plates and can be moved to different locations on the robot deck. Even if the software controlling the robot could make the multiple height calibrations required, the operator would be required to conduct the calibration every time the plate or probe is relocated or replaced.
Sample delivering robotic systems become more complicated when multiple probes (e.g., a one by four row) which move in the Z direction (i.e., up or down) with respect to the robot deck are used in the system, particularly when such probes are rigidly attached to a robotic arm. Even if the multiple probes could be perfectly aligned to each other, only one probe would theoretically be positioned in a plane parallel with the receiving sample plate. Because the row of probe tips will not be in a parallel plane, the distance from tips to plate will vary. If the distance is too great, the droplet of sample will not touch the plate and hence the liquid sample will not spot. Conversely, if there is no distance between the probe and plate, or if this distance is too close, then the chemistry previously deposited on the surface could be damaged or the sample may not deposit or deposit off position. Variations that result from manufacturing the robotic system, the racks and the sample plates have proven to be too great to attain the perfect relative positioning between a sample plate and an array of multiple probes. Matters are even more complicated when probes that are assembled as a three-dimensional array, for example in a four by four arrangement, are moved in the Z direction.
It would be desirable to provide a robotic apparatus, system and process which includes an array of multiple probes for delivering liquid samples which can be positioned at a desired position quickly and automatically. In addition, it would be desirable to provide such an apparatus, system and process wherein the multiple probes can be accurately positioned simultaneously rather than individually.
This invention provides an array of probes capable of simultaneously delivering a plurality of samples to a substrate surface wherein the distance between the outlet end of each probe and the substrate surface is essentially the same for each probe. This distance can be accurately controlled each time the substrate surface is replaced with a new substrate surface. The probes are slidably mounted within a probe housing such that the outlet end of each probe is exposed to allow interaction with the substrate surface, and a wall of the probe is contacted with a friction element which exerts a friction force on the probe to retain the probe in place within the housing. In one embodiment, the probes are hollow tubes and an inlet end of the probe is secured to a flexible conduit which permits movement of the probe and which delivers fluid to the probe or removes fluid from the probe. Movement of the probes from an initial position is effected by the application of a second force that is sufficient to overcome the friction force exerted on the probe wall. When the second force is no longer applied to the probes, the friction force retains the probes at a new position.
For the fluid dispense embodiment discussed above, a cycle for using the probe comprises drawing a vacuum within the probe through the flexible conduits in order to aspirate air into the probes. The air functions as a barrier between a wash liquid and a liquid sample within the probe. The robotic system positions the probe housing over the MTP to allow the probes to aspirate liquid sample from the MTP. Thereafter the probe housing is positioned over a MALDI sample plate and the probe housing is lowered such that the probes are then allowed to contact the surface of the sample plate. The force applied to lower the probes is sufficiently large to overcome the friction force exerted by the friction element so that the probes are moved to come in contact with the substrate surface. Since the position of the substrate surface within the robotic system is almost always nonparallel with the ends of the probes, the outlet ends of the probes will be in different positions and thus the robotic system overdrives the lowering probes to make sure that each probe in the array comes in contact with the substrate surface. The probes are then raised to position the outlet ends of each of the probes at a desired distance from the substrate surface, such as about 0.01 inch from the surface. A positive pressure is then applied to the probe so that the liquid samples are deposited on the substrate surface, such as on a plurality of shallow wells on the MALDI sample plate surface. The probe housing is then raised and a plate integral with the probe housing contacts a fixed surface which moves and resets the probes to their initial position. The probes are then directed to a waste container whereupon the pressure within the probe is increased in order to deliver wash liquid from the flexible conduits through the probes to render them sufficiently clean to process additional samples without contamination. The cycle then is repeated with a replacement sample plate being positioned within the robotic system for sample spotting.
The use of the friction element and the fixed surface to reset the probes permits repeated use of the probes wherein the probes are moved simultaneously to adjust to the surface configuration of a given substrate surface without the need to calibrate the position of each probe individually.